Mitochondria-Mediated Apoptosis of HCC Cells Triggered by Knockdown of Glutamate Dehydrogenase 1: Perspective for Its Inhibition through Quercetin and Permethylated Anigopreissin A

Metabolic reprogramming is a hallmark of cancer cells required to ensure high energy needs and the maintenance of redox balance. A relevant metabolic change of cancer cell bioenergetics is the increase in glutamine metabolism. Hepatocellular carcinoma (HCC), one of the most lethal cancer and which requires the continuous development of new therapeutic strategies, shows an up-regulation of human glutamate dehydrogenase 1 (hGDH1). GDH1 function may be relevant in cancer cells (or HCC) to drive the glutamine catabolism from L-glutamate towards the synthesis of alpha-ketoglutarate (alpha-KG), thus supplying key tricarboxylic acid cycle (TCA cycle) metabolites. Here, the effects of hGLUD1 gene silencing (siGLUD1) and GDH1 inhibition were evaluated. Our results demonstrate that siGLUD1 in HepG2 cells induces a significant reduction in cell proliferation (58.8% +/- 10.63%), a decrease in BCL2 expression levels, mitochondrial mass (75% +/- 5.89%), mitochondrial membrane potential (30% +/- 7.06%), and a significant increase in mitochondrial superoxide anion (25% +/- 6.55%) compared to control/untreated cells. The inhibition strategy leads us to identify two possible inhibitors of hGDH1: quercetin and Permethylated Anigopreissin A (PAA). These findings suggest that hGDH1 could be a potential candidate target to impair the metabolic reprogramming of HCC cells.

Automated summary

Metabolic reprogramming is crucial for cancer cells to meet high energy needs and maintain redox balance, with glutamine metabolism playing a key role. In the study of hepatocellular carcinoma, up-regulation of GDH1 was observed, and inhibition of this enzyme showed promising results in reducing cell proliferation and identifying potential inhibitors. These findings suggest that targeting hGDH1 could be a viable strategy to disrupt the metabolic reprogramming of HCC cells.